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Project Proposal for International Science
and TITLE: STUDY OF THE RED BLOOD SYSTEM,
NEUROVEGETATIVE STATUS AND THE BRAIN INTEGRATIVE ACTIVITY IN ANIMALS WITH A
VIEW TO REVEALING NEW CRITERIA OF BIOINDICATION OF ACUTE AND REMOTE
CONSEQUENCES OF IONIZING-RADIATION EFFECTS Summary Basic goal
of the submitted Project is the detection in laboratory animals of new
diagnostic criteria and their prognostic value for the estimation of acute
and remote consequences of the effect of ionizing radiation in sublethal
doses, as well as development of new and perfection of the known noninvasive
and inexpensive methods for mass exploration of persons of increased
radiation risk. Using original complex evaluations of hematological and
neurobiological studies, it is intended to determine adaptive resources of
irradiated animals and their offsprings from the point of view of the degree
of rehabilitation, including the biological and social value of populations.
Three basic principles underlie the ideology of the Project: 1) The
possibility of extrapolating the results of experimental studies for the
estimation of acute and remote consequences of radiation injury and the risk
rate for people, 2) Establishment of new and perfection of the known
noninvasive and inexpensive criteria for the evaluation of radiation
consequences, applicable for a mass exploration of people and resolution of
other similar tasks, including the ecological and epidemiological ones, 3)
The possibility of a maximal automatization of the used methods with a view
to facilitating and standardizing mass investigations, as well as formation
of data base and archives for further computer generalization of large arrays
of information. The occurred
and potential radionuclide disasters necessitate deepening of knowledge in
the area of the biological action of ionizing radiation and estimation of the
degree of risk for the health of those who had suffered and for their
posterity. The Chernobyl tragedy, which, according to SRC RBE data, affected,
to a considerable extent, also Western Georgia [1-5], keeps in tension
millions of people in various countries. This is associated not only with the
psychological tension, but also with the objective disturbances of health of
a large population of people affecting their psychic and social stability.
Clinical examination of a tremendous contingent and affording them a
qualified assistance at the update level is an exorbitant burden placed on
the economy and human resources of the countries to have suffered. If one
takes into account labor-intensiveness and expensiveness of similar
systematic examinations, particularly actual renders selection of the most
informative noninvasive methods of check-up of population. Similar tasks are
posed in the zones of ecological and social crises of various origin. As shown by
investigations, undertaken by SRC RBE, studying acute and remote consequences
of radiation injury and at the experimental modelling of these processes the
most informative and accessible may prove to be a complex analysis of a
minimal set of hematological, cardiological and neurobiological criteria. In
this connection the Project shall be realized as a unified common ideology of
three sections, involving the following trends and criteria for the
evaluation of acute and remote consequences of radiation injury: Hematological
criteria. Changes in the blood-forming
system is known to be universal criteria of estimating the severity of
radiation injury and the degree of recovery. The red blood system (RBS),
however, appears not to be studied in this respect sufficiently well yet.
Pursuant to recent data number of the glycophorine-A mutant erythrocytes are
virtually linearly dependent on the dose received and may be used for the
biological dosimentry in any period of life [6]. A model has also been made
of the division of brainstem cells through the withdrawal of mutant
erythrocytes [7]. Our investigations demonstrated that analysis of population spectra of PBE provides far greater diagnostically and prognostically important information than it has been known so far. In this section of the Project it is intended to create a principally new methodology on the basis of elaborated by us methods for the estimation of RBS functional state by the characteristic dynamics of changes in the PBE population spectra. The methodology relies on an original principle of investigation of relaxation processes at the erythrocyte volume variation under conditions of their gradual and reversible spherulation. The general theoretical premises, a body of mathematics and algorithmic base of the principle are described in a number of papers and in a monograph [8-15] and is also available in the SRC RBE Internet Web-site: A NEW METHOD FOR STUDYING THE RED BLOOD SYSTEM The
methodology rests on the theoretically correct and experimentally verified
assumption that the families of PBE population spectra and the dynamics of
alteration of the pattern of erythrocyte volumes relaxation under conditions
of gradual reversible spherulation reflect adequately not only the degree of
tension of functional activity of adaptive, compensatory and reparatory
mechanisms of RBS, but also of the whole body. This methodology will make it
possible: 1) to
determine the speed and quality of the erythrocyte maturing and to evaluate
the state of erythropoiesis of the pool of brainstem cell, not resorting to
the exploration of bone marrow punctates and complex hematological studies. 2) to
determine the rate of physiological aging of cells (biological age), the
extent of functional and pathological modification (wearing) of the
erythocytes' structural elements (physical) or chronological age), to
estimate the rate of aging and elimination of cells having exhausted the
biological resource, as well as to judge about the metabolic demands and
abilities of the body in order to renovate and maintain biological full-value
of the circulating and deposited erythrocyte population. 3) to
estimate the functional state of the red cell membranes and oxygen density of
erythrocyte hemoglobin in various age groups and judge about the rheological
properties and metabolic efficiency of circulating blood. 4) to
evaluate behavior of interdependence depot-circulation and define the
summated reserve possibilities of adaptation mechanisms at the functional
loadings on metabolism. 5) to define
the RBS response at pharmacological or any other activation or depression of
erythropoiesis. 6) to define
radiation dose, observation period, etc dependent variation of erythrocyte
mean life span. The methodology
can be widely applied not only in hematological, but also in general medical
practice, including diagnostics and evaluation of efficiency of therapeutic
measures in the very diverse diseases, doping control with the use of
erythropoietins or hemotransfusion, for the estimation of physical condition
of schoolchildren, trainage of sportsmen, professional preparation of
service-men and in the case of selection of adequate representative groups -
it can be applied for objective estimation of life quality of population of
states and regions. The methodoly under consideration shall be realized as an
integral complex of systems engineering hardware-software. Besides, on the
strength of experimental findings, an experimental model was made of PBE,
which will enable computer imitation of adaptive changes. The
biomedical procedure of the developed method is maximally simplified,
standardized and may be combined with the routine hematological
investigation, for it requires no more than 15 m l blood. The methodology may
have a multipurpose application to various investigations, involving
monitoring of the population life quality. In the world literature the
analogous systems are not known. Neurovegetative
criteria. The vegetative nervous
system is responsible for the control over all the processes of survival and
subtly reacts to the variation of adaptive demands of the body depending on
the changes of internal and external environment. This is reflected in the
vagosympathetic balance of short-lasting (functional) and stationary
character depending on the adaptation to the altered conditions of habitation
environment or development of prolonged tension of regulation system during
dysfunctions and pathological processes. The world scientific practice of
recent years has shown that for the investigation of neurovegetative status
rather effective and informative appears to be the method of analysis of
heart rate variability (HRV) and respiration. General principles were
elaborated for physiological interpretation of HRV data in humans and
estimation of cardiological risk, including the diagnostic standards [16].
There are no analogous data for laboratory animals, although there exist
separate publications devoted to these issues [17-19]. Our Center
has a great experience in radiobiological investigations of this kind
[20-25]. In particular, it has been demonstrated that population of rats and
rabbits even of one and the same litter are not homogeneous by the
vagosympathetic balance and among them as in humans one can distinctly
distinguish vagotonics, normotonics and sympathicotonics. These latter appear
to be far more radiosensitive, that should be taken into account while making
professional selection of persons bound with radiation risk. Exposure to
lethal doses of ionizing radiation elicits specific changes in the
vago-sympathetic balance with a characteristic dynamics. This and a number of
other data obtained by us lend support to the consideration that the
investigation of variability of cardiac and respiratory rhythms turns out to
be perspective for the manifestation of changes in the neurovegetative status
in acute and remote periods of radiation injury. Behavioral
and neurochemical criteria. A
great body of investigations deals with the effect of ionizing radiation on
the CNS. The world literature, collected by us in a specialized data base,
bibliographic part of which published as a separate book [26] includes more
than 4 thousand papers, reviews and monographs. Nevertheless, remote
neurobiological effects have been insufficiently studied yet, especially from
the position of alteration of the function of brain integrity and its
integrative activity. There are but a small number of works in which late
changes mainly morphological, were revealed in the neural-glial architecture,
the glia-vascular interrelations, as well as demyelinzation of nerve fibers,
a decrease in the number of neurons, development of gliosis, etc.
Dose-dependence of these changes and time of their manifestion have not been
clearly defined yet. Posterity of irradiated animals have not practically
been studied in this respect. The changes
detected by us in the brain integrative activity in the irradiated animals
have exact neurochemical correlates in the form of characteristic alteration
of quantitative content, distribution and ratio of a number of biologically
active substances (mediator amino acids, biogenic amines, receptors, etc) in
different brain structures and the blood serum. Morphological, including
histochemical, as well as neurochemical investigations have demonstrated that
in an absolute majority of animals survived after radiation these changes
occur like accelerated aging and end in premature death. What kind of changes
occur in the above-indicated neurobiological criteria in a remote period of
radiation injury, whether they manifest themselves at the exposure to small
doses, whether they affect the biological full value of irradiated animals'
posterity are not known yet. Effective use
of the above-mentioned set of hematological, behavioral, neurovegetative and
neurobiological criteria and a complex analysis of the results, as well as
taking into account great experience of work of SRC RBE in the field,
professional skill of investigators, informational maintenance and equipment
with machinery, all this give grounds to believe that the Project at large
will be successfully realized. References ·
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Situation in ·
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L.Intskirveli, S.Kirtadze,J.Mandjgaladze, L.Mosulishvili, T.Sanaia,
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State of Environment in the Caucasian Region. Part 3: The preliminary
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Signal X-Irradiation in Sublethal Doses on Heart Rate Variability (HRV) and
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I.Maisuradze, L.Tsitskishvili, G.Magradze Action of the Whole-body
X-Irradiation in Sublethal and Superlethal Doses on Spontaneous and Induced
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